Successful pregnancy requires normal folliculogenesis and ovulation followed by adequate morphologic development of the secretory endometrium, successful implantation of the blastocyst and continued support by the corpus luteum. Progesterone appears to play a critical role in these processes. We have recently shown that it appears to be the ovarian message that signals follicular maturity to the pituitary gland, and thus acts as the ultimate trigger for the midcycle LH surge that results in ovulation. Progesterone also seems essential to the induction of a variety of endometrial proteins that may play important roles in implantation. One of these, placental protein 14, a luteal phase product of the glands that is secreted into the uterine lumen and bloodstream, has been proposed as a marker of progesterone action on the endometrium. We have shown that concentrations of PP 14 are reduced in non-pregnant women receiving small daily doses of the progesterone antagonist RU 486 and that normal development of the endometrium is delayed. These studies confirm that progesterone is essential for functional and structural development of the endometrium. Future work will concentrate on the temporal pattern of endometrial messenger RNA and protein production during the cycle to understand the mediators and results of gonadal steroid action. These studies promise to increase our understanding of normal endometrial physiology as well as abnormal implantation, recurrent abortion and infertility. The guinea pig, like women, requires progesterone for normal endometrial maturation, implantation and pregnancy. We have used RU 486 to probe the process of implantation in this animal model. Small daily doses of the drug completely prevent implantation sites, confirming the critical role of progesterone in nidation. These results are the first to show that small daily doses of antiprogestins can prevent pregnancy. Taken with the above results in women, these studies suggest that administration of antiprogestin agents in a small daily dose represents a novel approach to human contraception.